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Anti-CD3 & Anti-CD7 Ricin A Immunotoxin-Combination for Acute Graft Versus Host Disease

Primary Purpose

Acute Graft Versus Host Disease

Status

Withdrawn

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

IT-Combination

About this trial

This is an interventional treatment trial for Acute Graft Versus Host Disease focused on measuring acute GVHD, immunotoxin, anti-CD3, anti-CD7, Ricin A

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients suffering from severe acute GVHD (Grade II-IV) progressing after 3 days, or non-improving after 5 days, of prednisolone at 2 mg/kg a day.
Age ≥ 18 years.
Patients or their guardians should have given written informed consent using forms approved by the Institutional Review Board.

Exclusion Criteria:

Patients receiving concomitant investigational therapeutics/prophylaxis for acute GVHD at the time of enrollment.
Patients with histological signs/symptoms suggestive of chronic GVHD.
Patients requiring mechanical ventilation, requiring vasopressor support, requiring hemodialysis, having serum creatinine > 266 μmol/l (> 3 mg/dl), or having a serum albumin level of 20 g/l or less.
Patients having uncontrolled bacterial, viral or fungal infections at the start of therapy.
Patients with current evidence of active intrapulmonary disease.
Patients with known hypersensitivity to any of the components of the study drug (murine mAb or RTA).
Patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study.

Sites / Locations

Department of Hematology Radboud University Nijmegen (RUN)
Department of Hematology Erasmus MC/Daniel den Hoed Cancer CenterGroene Hilledijk
L.F. , Department of HematologyUMC Utrecht

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm Description

Treatment arm

Outcomes

Primary Outcome Measures

The acute GVHD response rate on study Day 29

Secondary Outcome Measures

The safety and tolerability of the IT-combination, as determined by the number and intensity of adverse and serious adverse events during 12 months

The acute GVHD relapse rate

The incidence of chronic GVHD during 12 months

The overall survival and progression free survival during 12 months

The kinetics of treatment-induced T cell and Natural Killer (NK) cell depletion

The pharmacokinetic profile of the IT-combination

The occurrence and extent of humoral responses against the IT-combination

The occurrence of any treatment-induced cytokine release

Full Information

NCT ID

NCT00640497

First Posted

March 4, 2008

Last Updated

April 28, 2009

Sponsor

Henogen

1. Study Identification

Unique Protocol Identification Number

NCT00640497

Brief Title

Anti-CD3 & Anti-CD7 Ricin A Immunotoxin-Combination for Acute Graft Versus Host Disease

Official Title

A Phase I/II Multicentric Study to Determine the Safety and Efficacy of a Combination of Anti-CD3 & Anti-CD7 Ricin A Immunotoxins for the Treatment of Steroid-Resistant Acute Graft-Versus-Host Disease

Study Type

Interventional

2. Study Status

Record Verification Date

April 2009

Overall Recruitment Status

Withdrawn

Why Stopped

Unavailability of investigational product

Study Start Date

January 2010 (undefined)

Primary Completion Date

January 2012 (Anticipated)

Study Completion Date

January 2012 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor

Henogen

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

In this study, a combination of two T-cell directed antibodies both conjugated to a cell-killing toxin will be evaluated. Previous in vitro studies have demonstrated that this so-called immunotoxin-combination (IT-combination) acts synergistically in eliminating T cells. In a subsequent clinical pilot-study, the IT-combination has generated encouraging results when applied as third line therapy. Extensive biological and clinical responses could be noted in the absence of severe acute toxicities. Building on this experience, the current study aims at evaluating the characteristics of the IT-combination when administered in an earlier phase of the disease, i.e. as second line instead of as third line therapy.

Detailed Description

"The experimental design is a non-controlled multicentric fixed-dose Phase I/II study. A total of 12 evaluable patients will be enrolled in 4 transplant centers throughout the Netherlands, in a 9 to 12 months period. The treatment consists of a standard dose of 4 infusions IT-combination (4 mg/m2), given 48-hours apart over a 4-hour period. The intended follow-up period is 12 months. The patient will also be asked to participate in additional research aiming at determining the presence and evolution of biomarkers suggestive for the extent to which the IT-combination 'resets the T-cell compartment, induces clinical tolerance, and/or enhances the risk of over-immunosuppression."

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Graft Versus Host Disease

Keywords

acute GVHD, immunotoxin, anti-CD3, anti-CD7, Ricin A

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Treatment arm

Intervention Type

Biological

Intervention Name(s)

IT-Combination

Intervention Description

The treatment consists of a standard dose of 4 infusions of IT-combination (4 mg/m2), given 48-hours apart over a 4-hour period. The IT-combination is a combination of two immunotoxins. One immunotoxin is a mAb anti-CD3 conjugated to recombinant ricin A chain and the other immunotoxin is a mAb anti-CD7 conjugated to recombinant ricin A chain.

Primary Outcome Measure Information:

Title

The acute GVHD response rate on study Day 29

Time Frame

Day 29

Secondary Outcome Measure Information:

Title

The safety and tolerability of the IT-combination, as determined by the number and intensity of adverse and serious adverse events during 12 months

Time Frame

12 months

Title

The acute GVHD relapse rate

Time Frame

12 months

Title

The incidence of chronic GVHD during 12 months

Time Frame

12 months

Title

The overall survival and progression free survival during 12 months

Time Frame

12 months

Title

The kinetics of treatment-induced T cell and Natural Killer (NK) cell depletion

Time Frame

12 months

Title

The pharmacokinetic profile of the IT-combination

Time Frame

day 9

Title

The occurrence and extent of humoral responses against the IT-combination

Time Frame

12 months

Title

The occurrence of any treatment-induced cytokine release

Time Frame

day 7

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients suffering from severe acute GVHD (Grade II-IV) progressing after 3 days, or non-improving after 5 days, of prednisolone at 2 mg/kg a day. Age ≥ 18 years. Patients or their guardians should have given written informed consent using forms approved by the Institutional Review Board. Exclusion Criteria: Patients receiving concomitant investigational therapeutics/prophylaxis for acute GVHD at the time of enrollment. Patients with histological signs/symptoms suggestive of chronic GVHD. Patients requiring mechanical ventilation, requiring vasopressor support, requiring hemodialysis, having serum creatinine > 266 μmol/l (> 3 mg/dl), or having a serum albumin level of 20 g/l or less. Patients having uncontrolled bacterial, viral or fungal infections at the start of therapy. Patients with current evidence of active intrapulmonary disease. Patients with known hypersensitivity to any of the components of the study drug (murine mAb or RTA). Patients who are pregnant, breast feeding, or, if sexually active, unwilling to use effective birth control for the duration of the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Anton V Schattenberg,, MD, PhD,

Organizational Affiliation

Department of Hematology Radboud University Nijmegen (RUN) Medical Centre

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Hematology Radboud University Nijmegen (RUN)

City

Nijmegen

ZIP/Postal Code

6525 GA

Country

Netherlands

Facility Name

Department of Hematology Erasmus MC/Daniel den Hoed Cancer CenterGroene Hilledijk

City

Rotterdam

ZIP/Postal Code

3153075 EA

Country

Netherlands

Facility Name

L.F. , Department of HematologyUMC Utrecht

City

Utrecht

ZIP/Postal Code

1003584 CX

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

10845899

Citation

van Oosterhout YV, van Emst L, Schattenberg AV, Tax WJ, Ruiter DJ, Spits H, Nagengast FM, Masereeuw R, Evers S, de Witte T, Preijers FW. A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease. Blood. 2000 Jun 15;95(12):3693-701.

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Anti-CD3 & Anti-CD7 Ricin A Immunotoxin-Combination for Acute Graft Versus Host Disease

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